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Attention Deficit Hyperactivity Disorder (ADHD) medication is increasingly being used during pregnancy. Concerns have been raised as to whether ADHD medication has long-term adverse effects on the offspring. The authors investigated whether in utero exposure to ADHD medication was associated with adverse long-term neurodevelopmental and growth outcomes in offspring. The population-based cohort study in the Danish national registers included 1,068,073 liveborn singletons from 1998 to 2015 followed until any developmental diagnosis, death, emigration, or December 31, 2018. Children of mothers who continued ADHD medication (methylphenidate, amphetamine, dexamphetamine, lisdexamphetamine, modafinil, atomoxetine, clonidine) during pregnancy and children of mothers who discontinued ADHD medication before pregnancy were compared using Cox regression. Main outcomes were neurodevelopmental psychiatric disorders, impairments in vision or hearing, epilepsy, seizures, or growth impairment during childhood or adolescence. In total, 898 children were exposed to ADHD medication during pregnancy compared to 1270 children whose mothers discontinued ADHD medication before pregnancy. After adjustment for demographic and psychiatric characteristics of the mother, no increased risk of any offspring developmental disorders was found combined (aHR 0.97, 95% CI 0.81 to 1.17) or for separate subcategories. Similarly, no increased risk was found for any sub-categories of outcomes in the negative control or sibling controlled analyses. Neurodevelopment and growth in offspring do not differ based on antenatal exposure to ADHD medication. These findings provide reassurance for women with ADHD who depend on ADHD medication for daily functioning and who consider continuing medication in pregnancy.

Attention-Deficit Hyperactivity Disorder (ADHD) is a complex and heterogeneous neurodevelopmental condition for which curative treatments are lacking. Whilst pharmacological treatments are generally effective and safe, there is considerable inter-individual variability among patients regarding treatment response, required dose, and tolerability. Many of the non-pharmacological treatments, which are preferred to drug-treatment by some patients, either lack efficacy for core symptoms or are associated with small effect sizes. No evidence-based decision tools are currently available to allocate pharmacological or psychosocial treatments based on the patient’s clinical, environmental, cognitive, genetic, or biological characteristics. We systematically reviewed potential biomarkers that may help in diagnosing ADHD and/or stratifying ADHD into more homogeneous subgroups and/or predict clinical course, treatment response, and long-term outcome across the lifespan. Most work involved exploratory studies with cognitive, actigraphic and EEG diagnostic markers to predict ADHD, along with relatively few studies exploring markers to subtype ADHD and predict response to treatment. There is a critical need for multisite prospective carefully designed experimentally controlled or observational studies to identify biomarkers that index inter-individual variability and/or predict treatment response.

Objective: Aggression is a common, yet complex, behavioral complaint, and a frequent indication for referral to child and adolescent psychiatrist treatment. This article reviews the evidence supporting pharmacotherapy of aggression in youth, with a primary focus on impulsive aggression (the primary indication for this intervention). Relevant diagnostic considerations and consensus guidelines are discussed. Methods: Articles examining the role of medications in the treatment of aggression in youth with pathological aggression were identified using PubMed and MEDLINE® databases over the past 15 years (2000–2015); selected articles published prior to 2000 and deemed to be of high relevance were searched and also included. Search terms included: Aggression, aggressive, disruptive behavior, conduct, youth, children, and adolescents. Cited references were also searched for relevant articles. Results: There are a number of evidence-based medication treatments for aggression, which are generally best considered in the context of differential diagnosis and ongoing evidence-based psychosocial interventions. Impulsive aggression is generally considered the type of aggression most amenable to medication, but other aggression subtypes may also possibly respond to treatment. Medication classes with positive evidence include the psychostimulants and α-2 agonists (in the presence of attention-deficit/hyperactivity disorder [ADHD] and/or disruptive behavior disorders), mood stabilizing agents, and atypical antipsychotics. Published guidelines recommend systematic and adequate trials of medications in sequential order, to optimize response and minimize polypharmacy. Guidelines for safety monitoring are available for many of the medications used for aggression in youth, and are also discussed. Conclusions: Aggression in children carries a high risk of poor outcomes, and, therefore, a better understanding of treatment options is a high priority. The available literature points to the importance of identifying the underlying disorder, when possible, and using this information to guide treatment selection. Future studies are needed to better inform the treatment of aggression across disorders, and the treatment of different aggression subtypes.

Brain dopamine dysfunction in attention deficit/hyperactivity disorder (ADHD) could explain why stimulant medications, which increase dopamine signaling, are therapeutically beneficial. However while the acute increases in dopamine induced by stimulant medications have been associated with symptom improvement in ADHD the chronic effects have not been investigated. We used positron emission tomography and [(11)C]cocaine (dopamine transporter radioligand) to measure dopamine transporter availability in the brains of 18 never-medicated adult ADHD subjects prior to and after 12 months of treatment with methylphenidate and in 11 controls who were also scanned twice at 12 months interval but without stimulant medication. Dopamine transporter availability was quantified as non-displaceable binding potential using a kinetic model for reversible ligands. Twelve months of methylphenidate treatment increased striatal dopamine transporter availability in ADHD (caudate, putamen and ventral striatum: +24%, p<0.01); whereas there were no changes in control subjects retested at 12-month interval. Comparisons between controls and ADHD participants revealed no significant difference in dopamine transporter availability prior to treatment but showed higher dopamine transporter availability in ADHD participants than control after long-term treatment (caudate: p<0.007; putamen: p<0.005). Upregulation of dopamine transporter availability during long-term treatment with methylphenidate may decrease treatment efficacy and exacerbate symptoms while not under the effects of the medication. Our findings also suggest that the discrepancies in the literature regarding dopamine transporter availability in ADHD participants (some studies reporting increases, other no changes and other decreases) may reflect, in part, differences in treatment histories.

Attention deficit hyperactive disorder (ADHD) is a highly heritable neurodevelopmental disorder, and excessive daytime sleepiness is frequently observed in ADHD patients. Excessive daytime sleepiness is also a core symptom of narcolepsy and essential hypersomnia (EHS), which are also heritable conditions. Psychostimulants are effective for the symptomatic control of ADHD (primary recommended intervention) and the two sleep disorders (frequent off-label use). However, the common biological mechanism for these disorders has not been well understood. Using a previously collected genome-wide association study of narcolepsy and EHS, we calculated polygenic risk scores (PRS) for each individual. We investigated a possible genetic association between ADHD and narcolepsy traits in the Hamamatsu Birth Cohort for mothers and children (HBC study) ( n  = 876). Gene-set enrichment analyses were used to identify common pathways underlying these disorders. Narcolepsy PRS were significantly associated with ADHD traits both in the hyperactivity domain (e.g., P -value threshold < 0.05, β [SE], 5.815 [1.774]; P  = 0.002) and inattention domain (e.g., P -value threshold < 0.05, β [SE], 5.734 [1.761]; P  = 0.004). However, EHS PRS was not significantly associated with either domain of ADHD traits. Gene-set enrichment analyses revealed that pathways related to dopaminergic signaling, immune systems, iron metabolism, and glial cell function involved in both ADHD and narcolepsy. Findings indicate that ADHD and narcolepsy are genetically related, and there are possible common underlying biological mechanisms for this relationship. Future studies replicating these findings would be warranted to elucidate the genetic vulnerability for daytime sleepiness in individuals with ADHD.

Stimulants (methylphenidate or amphetamines) are the recommended first-line option for the pharmacological treatment of individuals with attention deficit hyperactivity disorder (ADHD). However, some patients with ADHD will not respond optimally to stimulants. Here, we discuss strategies to manage stimulant-refractory ADHD, based on the recommendations advanced in clinical guidelines, knowledge of expert practice in the field, and our own clinical recommendations, informed by a comprehensive literature search in PubMed, PsycInfo, EMBASE + EMBASE classic, OVID Medline, and Web of Science (up to 30 March 2021). We first highlight the importance of stimulant optimization as an effective strategy to increase response. We then discuss a series of factors that should be considered before using alternative pharmacological strategies for ADHD, including poor adherence, time action properties of stimulants (and wearing-off of effects), poor tolerability (that prevents the use of higher, more effective doses), excessive focus on or confounding from presence of comorbid non-ADHD symptoms, and tolerance. Finally, we consider the role of non-stimulants and combined pharmacological approaches. While the choice of medication for ADHD is still to a large extent based on a trial-and-error process, there are reasonably accepted data and guidelines to aid in clinical decision-making. It is hoped that advances in precision psychiatry in the years ahead will further guide prescribers to tailor medication choice to the specific characteristics of the patient.

As virtual reality (VR) technology becomes increasingly prevalent, its potential for collecting objective behavioral data in psychiatric settings has been widely recognized. However, the lack of standardized methodologies limits reproducibility and data integration across studies, particularly in assessing attention-deficit/hyperactivity disorder (ADHD) and associated behaviors, such as irritability and aggression. This study examines the use of VR-based movement data to operationalize core ADHD symptoms (hyperactivity and inattention) and comorbid disruptive behaviors (irritability and aggression), aiming to identify reproducible and clinically actionable metrics and evaluate their explanatory power for each symptom domain to assess the overall use of these variables. A total of 45 children (mean age 9.06, SD 2.11 years; n=14/45, 31% female) participated in the study and were divided into 2 groups: 28 (62%) diagnosed with ADHD and 17 (38%) controls. Seven VR-derived movement variables were analyzed: average speed, acceleration, total distance, area occupied, distance between the hands and head, frequency of movement, and time spent still. Correlation and stepwise regression analyses identified which variables best predicted ADHD symptoms and comorbid behaviors. Among the 7 VR-derived variables, average speed (mean r=0.460, SD 0.097) and total distance (mean r=0.442, SD 0.116) showed the broadest associations, each correlating with 8 measures. In contrast, frequency of movement was related only to hyperactivity (r=0.416; P=.004), suggesting strong but narrow predictive value. Stepwise regression identified total distance as the sole and strongest predictor of hyperactivity (R =0.411) and, except for participant-reported irritability, yielded significant models for all other measures (mean R =0.282, SD 0.064; all P<.05). This study provides empirical evidence on VR-derived movement variables that can inform the development of standardized methodologies for ADHD and comorbid behavior assessment. The identified metrics and their predictive patterns offer a basis for integrating VR-based measures into future research and clinical applications.

We examined real-world evidence on whether Lumosity, a remote digital health technology designed to deliver cognitive training to healthy adults, can improve cognition and reduce inattention in adults who reported having received a prior (lifetime) diagnosis of ADHD. Over the course of Lumosity training, this cohort of commercial users was assessed repeatedly online with a neuropsychological test battery (NCPT) and a scale of attention and mood in real-world contexts (BAMS-7). More Lumosity training between successive assessments led to greater improvements on the NCPT composite measure and the attentional subscale of the BAMS-7. This positive dose-response relation was found for six of eight NCPT subtests and three of four BAMS-7 attentional items. Additional findings support the participants’ clinical status and sensitivity of the assessments to ADHD symptoms. These findings provide evidence of cognitive and attentional benefits in a real-world cohort of adults reporting a lifetime diagnosis of ADHD from training with Lumosity under real-world conditions.

Zinc regulates dopaminergic signaling, and reduced serum zinc levels have been reported in individuals with ADHD. However, genetic associations between zinc and ADHD remain unclear. We examined this link using large-scale GWAS and molecular analyses across three cohorts: iPSYCH (14,584 ADHD cases and 22,492 controls), FAMHES ( n  = 1798), and the Hamamatsu Birth Cohort ( n  = 726). Two-sample Mendelian randomization revealed bidirectional associations between low serum zinc levels and ADHD diagnosis. Genetic correlation and polygenic risk score analyses supported this association. In the birth cohort, lower cord blood zinc were associated with higher ADHD symptom scores at ages 8–9. Zinc levels negatively correlated with IL-6 and maternal depressive symptoms. Directed acyclic graph analysis indicated that maternal stress increased IL-6, which reduced fetal zinc levels, linking to ADHD symptoms. These findings suggest low prenatal zinc may contribute to ADHD pathophysiology in genetically vulnerable children, potentially mediated by maternal stress and inflammation.

Attention-deficit/hyperactivity disorder (ADHD; also known as hyperkinetic disorder) is a common neurodevelopmental condition that affects children and adults worldwide. ADHD has a predominantly genetic aetiology that involves common and rare genetic variants. Some environmental correlates of the disorder have been discovered but causation has been difficult to establish. The heterogeneity of the condition is evident in the diverse presentation of symptoms and levels of impairment, the numerous co-occurring mental and physical conditions, the various domains of neurocognitive impairment, and extensive minor structural and functional brain differences. The diagnosis of ADHD is reliable and valid when evaluated with standard diagnostic criteria. Curative treatments for ADHD do not exist but evidence-based treatments substantially reduce symptoms and/or functional impairment. Medications are effective for core symptoms and are usually well tolerated. Some non-pharmacological treatments are valuable, especially for improving adaptive functioning. Clinical and neurobiological research is ongoing and could lead to the creation of personalized diagnostic and therapeutic approaches for this disorder. Attention-deficit/hyperactivity disorder (ADHD) is a neurodevelopmental disorder that typically starts in childhood. This Primer summarizes the epidemiology, mechanisms, diagnosis and treatment of ADHD.